Clinical characteristics: Fabry disease is the most common of the lysosomal storage disorders and results from deficient activity of the enzyme alpha-galactosidase A (α-Gal A), leading to progressive lysosomal deposition of globotriaosylceramide and its derivatives in cells throughout the body. The classic form, occurring in males with less than 1% α-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesia), the appearance of vascular cutaneous lesions (angiokeratomas), sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis), characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiac and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, females may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype.
In contrast, late-onset forms occur in males with greater than 1% α-Gal A activity. Clinical manifestations include cardiac disease, which usually presents in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy, arrhythmia, and proteinuria; renal failure, associated with ESRD but without the skin lesions or pain; or cerebrovascular disease presenting as stroke or transient ischemic attack.
Diagnosis/testing: Identification of deficient α-Gal A enzyme activity in plasma, isolated leukocytes, and/or cultured cells is the most efficient and reliable method of diagnosing Fabry disease in males. Identification of a hemizygous GLA pathogenic variant by molecular genetic testing confirms the diagnosis in a male proband. Identification of a heterozygous GLA pathogenic variant by molecular genetic testing establishes the diagnosis in a heterozygous female.
Management: Treatment of manifestations: Diphenylhydantoin, carbamazepine, or gabapentin to reduce pain (acroparesthesia); aspirin, lipid-lowering agents, and blood pressure control for cardiac ischemia; aspirin and/or other antiplatelet agents may be recommended for stroke prophylaxis; ACE inhibitors or angiotensin receptor blockers to reduce proteinuria; chronic hemodialysis and/or renal transplantation for ESRD; rehabilitation and hearing aids for auditory and vestibular symptoms; management of psychiatric manifestations per psychologist.
Prevention of primary complications – targeted therapies: Enzyme replacement therapy (ERT) with or without chaperone therapy (e.g., migalastat) to prevent and/or delay the progression of renal, cardiac, and cerebrovascular manifestations. Experts recommend that ERT be initiated as early as possible in all males with Fabry disease (including children and those with ESRD undergoing dialysis and renal transplantation) and in females with clinical disease manifestations, as all are at high risk for renal, cardiac, and cerebrovascular complications.
Surveillance: Annual assessment for angiokeratomas, acroparesthesia, sweating abnormalities, and gastrointestinal, pulmonary, and vascular manifestations; annual cardiology assessment with EKG and echocardiogram as recommended by cardiologist from age 18 years in males, biannual cardiology assessments in females from age 18 years; annual neurologic assessment with brain MRI\MRA every two to three years beginning at age 18 years; assessment of renal function including blood urea nitrogen, creatinine, and urinalysis annually or more frequently as needed; annual audiology evaluations in males beginning at age 18 years and biannually in females; psychological assessment beginning at age 18 years annually or more frequently as needed.
Agents/circumstances to avoid: Smoking. Amiodarone may or may not have detrimental effects in individuals with Fabry disease; evidence is insufficient.
Evaluation of relatives at risk: Early identification of affected male and female relatives by molecular genetic testing (if the GLA pathogenic variant in the family is known) or, in males only, measurement of α-Gal A enzyme activity (if the GLA pathogenic variant in the family is not known) in order to initiate appropriate management as early as possible in affected individuals.
Genetic counseling: Fabry disease is inherited in an X-linked manner: hemizygous males are affected; heterozygous females may be as severely affected as males or asymptomatic throughout a normal life span. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. If a male is the only affected family member, his mother is likely heterozygous for the GLA pathogenic variant; rarely, a single affected male in a family may have a de novo pathogenic variant. A heterozygous female has a 50% chance of transmitting the GLA pathogenic variant in each pregnancy. An affected male transmits the pathogenic variant to all his daughters and none of his sons. Once the GLA pathogenic variant has been identified in an affected family member, molecular genetic testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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